We demonstrate that the BRAFV600E–TFEB/ZKSCAN3–autophagy–lysosomal axis represents a key regulatory pathway through which BRAFV600E orchestrates TGF-β signaling and EMT, resulting in tumor progression, metastasis, and resistance to BRAF-targeted therapy in melanoma (Supplementary Fig. 12). The gene discussed is TFEB; the disease is melanoma.